Arteriosclerosis is a class of diseases characterized by the thickening and hardening of the arterial walls of blood vessels. Although all blood vessels are susceptible to this serious degenerative condition, the aorta and the coronary arteries serving the heart are most often affected. Arteriosclerosis is of profound clinical importance since it can increase the risk of heart attacks, myocardial infarctions, strokes, and aneurysms.
The traditional treatment for arteriosclerosis includes vascular recanalization procedures for less-serious blockages and coronary bypass surgery for major blockages. Where possible, vascular recanalization is much preferred to coronary bypass because it is a far less invasive procedure. Vascular recanalization procedures involve using intravascular devices threaded through blood vessels to the obstructed site, and include, for example, percutaneous transluminal coronary balloon angioplasty (PTCA), also known as balloon angioplasty, and stents. Balloon angioplasty uses a catheter with a balloon tightly packed onto its tip. When the catheter reaches the obstruction, the balloon is inflated, causing the atherosclerotic plaques to become compressed against the vessel wall, and resulting in improved blood flow. However, a serious shortcoming of this and other intravascular procedures is that, in a significant number of treated individuals, some or all of the treated vessels restenose (i.e., re-narrow). For example, restenosis of an atherosclerotic coronary artery after PTCA occurs in 10-50% of patients undergoing this procedure and subsequently requires either further angioplasty or a coronary artery bypass graft. Furthermore, restenosis of an atherosclerotic coronary artery after stenting occurs in 10-20% of patients undergoing this procedure and subsequently requires repeat treatments to maintain adequate blood flow through the affected artery. Restenosis generally occurs in a relatively brief time period, e.g., roughly less than six months, after treatment.
While the exact hormonal and cellular processes promoting restenosis have not been determined, restenosis is thought to be due in part to mechanical injury to the walls of the blood vessels caused by the balloon catheter or other intravascular device. For example, the process of PTCA, in addition to opening the obstructed artery, also injures resident coronary arterial smooth muscle cells (SMCs). In response to this injury, adhering platelets, infiltrating macrophages, leukocytes, or the smooth muscle cells themselves release cell-derived growth factors such as platelet-derived growth factor (PDGF), with subsequent proliferation and migration of medial SMCs through the internal elastic lamina to the area of the vessel intima. Further proliferation and hyperplasia of intimal SMCs and, most significantly, production of large amounts of extracellular matrix over a period of three to six months results in the filling in and narrowing of the vascular space sufficient to significantly obstruct blood flow.
Several methods for inhibiting SMC proliferation following the use of an intravascular device have been reported in the patent literature. These include, for example, the local or systemic administration of anti-proliferative agents such as cell cycle inhibitors and anti-coagulant agents. However, systemic delivery of these agents requires doses that cause unacceptable side-effects or are prohibitively expensive. In addition, local delivery of agents such as heparin, as described in U.S. Pat. No. 4,824,436, has proven ineffective in inhibiting restenosis due in part to inadequate residence time of heparin at the site of injury. Cell cycle inhibitors such as taxol, which do not react covalently and therefore require prolonged residence time for effectiveness, suffer from similar problems. Moreover, prolonging residence times to increase the effectiveness of such treatments is also likely to present increased risks of toxicity.
Other methods reported for inhibiting SMC proliferation involve local delivery of active agents contained in a sustained-release formulation. For example, U.S. Pat. No. 5,171,217 describes active agents contained within a physiologically compatible, biodegradable polymeric microparticle. This formulation is delivered locally to the site of injury such that the agents are released from the arterial wall for 72 hours or more. An additional method for inhibiting SMC proliferation involves administering photochemically-activated agents by local delivery systems. For example, U.S. Pat. No. 5,354,774 describes locally delivering 8-methoxypsoralen to the site of injury and then activating a photodynamic reaction using a visible light source. Yet another approach for preventing SMC proliferation involves the use of radiation-emitting catheters or guide-wires. The radiation causes damage to the nucleic acid within SMCs, thereby inhibiting DNA replication and smooth muscle cell proliferation.
However, all of the above-described methods suffer from certain significant drawbacks. For example, sustained release formulations require the incorporation of the active agent within a sustained release formulation. Photodynamic therapy requires both local delivery of the photo-active agent and the use of a complex intravascular light source. Delivery of a radiation dose requires the presence of a radiologist and presents exposure hazards to the attending personnel, as well as material storage, handling, and disposal complications.
A significant drawback to the uncoated and drug-coated coronary stents now on the market or in clinical trials lies in their failure to inhibit thrombosis in the vicinity of the deployed stent. For example, thrombosis has been observed in human clinical trials when using stents coated with either taxol or rapamycin. To prevent such thrombosis, patients have had to undergo anti-coagulation treatment for a two- to three-month duration. Another significant drawback is that inflammation still occurs following stent placement.
Thus, there is a need to develop a safe and effective intravascular device for inhibiting restenosis, thrombosis, and/or inflammation in a patient following vascular intervention with the device. The present invention satisfies this and other needs.